Reductive coupling of terpenic allylic halides catalyzed by Cp 2TiCl: A short and efficient asymmetric synthesis of onocerane triterpenes

Article abstract of DOI:10.1021/ol050335r

(Chemical Equation Presented) Titanocene chloride catalyzes the regioselective α,α′-homocoupling of terpenic allylic halides. This process has been employed in the short and effective synthesis of terpenoids such as β-onoceradiene (1), β-onocerin (2), and squalene (3). Evidence is presented for η¹-allyltitanium species being involved in the coupling.

Full text of DOI:10.1021/ol050335r

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2301-2304
Reductive Coupling of Terpenic Allylic
Halides Catalyzed by Cp2TiCl: A Short
and Efficient Asymmetric Synthesis of
Onocerane Triterpenes
Alejandro F. Barrero,* M. Mar Herrador, Jose´ F. Qu´ılez del Moral, Pilar Arteaga,
Jesu´s F. Arteaga, Mar´ıa Piedra, and Elena M. Sa´nchez
Department of Organic Chemistry, Institute of Biotechnology, UniVersity of Granada,
AVenida FuentenueVa, 18071 Granada, Spain
afbarre@goliat.ugr.es
Received February 17, 2005
ABSTRACT
Titanocene chloride catalyzes the regioselective
r
,
r′-homocoupling of terpenic allylic halides. This process has been employed in the short
and effective synthesis of terpenoids such as
species being involved in the coupling.
â
-onoceradiene (1), -onocerin (2), and squalene (3). Evidence is presented for
â
η
1-allyltitanium
To continue with our research into the use of bis(cyclopen-
tadienyl)titanium(III) chloride (Cp2TiCl) in the synthesis of
terpenoids,1 we report here on our achievements in the de-
velopment of a novel synthetic method based on a Ti(III)-
catalyzed carbon-carbon coupling of allylic halogenated
terpenoids (Scheme 1) and its application to the expeditious
homocoupling of benzylic and allylic halides.8 Bearing in
mind the mechanism of the above-mentioned reactions and
the broad range of functional groups tolerated (alcohols,
amines, amides, ketones, acids, esters),6d we thought that this
reagent might efficiently mediate the homocoupling of
terpenic allylic halides. A number of methods have already
been developed to perform the homocoupling of allylic and
alkyl halides9 such as the reductive coupling of allylic halides
by chlorotris(triphenylphosphine) cobalt(I)9g or Te2- species,9f
the reaction of allylic organometallic compounds with allylic
halides,9e the coupling of π-methallylnickel(I) bromide with
halides,9c the homocoupling of alkyl halides via activated
copper,9q and so on. In the field of terpenoid synthesis, the
Scheme 1. General Approach
(1) (a) Justicia, J. J.; Rosales, A.; Oller-Lo´pez, J. L.; Valdivia, M. V.;
Ha¨ıdour, A.; Oltra, J. E.; Barrero, A. F.; Ca´rdenas, D. J.; Cuerva, J. M.
Chem. Eur. J. 2004, 10, 1778-1788. (b) Barrero, A. F.; Cuerva, J. M.;
Herrador, M. M.; Valdivia, M. V. J. Org. Chem. 2001, 66, 4074-4078. (c)
Barrero, A. F.; Oltra, J. E.; Cuerva, J. M.; Rosales, A. J.Org. Chem. 2002,
67, 2566-2571. (d) Barrero, A. F.; Rosales, A.; Cuerva, J. M.; Oltra, J. E.
Org. Lett. 2003, 5, 1935-1938. (e) Barrero, A. F.; Cuerva, J. M.; AÄ lvarez-
Manzaneda, E. J.; Oltra, J. E.; Chahboun, R. Tetrahedron Lett. 2002, 43,
2793-2796.
synthesis of triterpenoids such as squalene (3) and onocerane
derivatives 1 and 2.2
Titanocene monochloride3 has been used in the past in
the homolytic opening of oxiranes4 and in pinacol coupling
reactions.5 This reagent has also provided good results in
the reduction of glycosyl bromides6 and Vic-dibromides.7
Furthermore, it has been reported that Cp2TiCl promotes the
(2) Connolly, J. D., Hill, R. A., Eds. In Dictionary of Terpenoids;
Chapman & Hall: London, U.K, 1991; Vol. 2, pp 1405-1406.
10.1021/ol050335r CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/14/2005

homocoupling reaction of allylic halides using Rieke barium10
is particularly interesting. This method has been reported to
give good results in the coupling of (E,E)-farnesyl barium
with farnesyl bromide,11 although its aplication has been
limited.
We started the development of this synthetic method by
choosing the simplest terpenic allyl halides: geranyl bromide
(4a) and its geometrical isomer neryl bromide (4b). When
these compounds were exposed to an excess of Cp2TiCl,12
the R,R′ coupling products (5a and 5b) were mainly obtained
after only 2 min, together with the R,γ′ adduct (Table 1,
entries 1 and 3).
in situ) to the corresponding halogenated derivative to give
an allylic radical species (I). This would then either dimerize
to give the coupling products 5 or suffer a second SET
process to give an η1-allyltitanium species (II), which would
react with a molecule of unaltered halogenated derivative
also to produce the coupling products 5 (Scheme 2).
Scheme 2
Table 1. Coupling of Allylic Bromidesa Using Cp2TiCl2/Mn
Evidence to help distinguish between the mechanistic paths
proposed may be inferred from a further analysis of the
results. Thus, although the geometry of the radical Ia might
not be suitable to lead to a 6-exo cyclization with the 6,7
double bond, its geometrical isomer Ib should give rise to
the formation of the corresponding p-menthanes. Since no
derivative p-menthanes were ever detected, the mechanism
via allyltitanium (II) would seem in principle more likely.13
Continuing with the mechanistic aspects of this reaction, we
prepared compounds 4c and 4d, in which the R,â-unsaturated
methyl ester group (better nucleophilic radical acceptor)
ought to favor the radical cyclization process.14 When these
R,â-unsaturated ester derivatives were made to react with
allylic
equiv of
time
ratioc
yielde
(%)
b
entry bromide Cp2TiCl2 (min) R,R′:R,γ′d compd
1
2
4a
4a
4b
4b
4c
4c
4d
4d
4c
4d
3
0.2
3
0.2
3
0.2
3
0.2
3
0.05
2
15
2
15
2
10
2
10
10
20
70:30
64:36
74:26
73:27
77:23
74:26
85:15
81:19
85:15
78:22
5a
5a
5b
5b
5c
5c
5d
5d
5c
5d
80
89
70
90
84
85
60
64
67
55
3
4
5
6
7
8
9f
10g
a Prepared by the reaction of corresponding alcohols with Ph3P/CBr4 in
benzene except for the commercially available geranyl bromide. b Performed
with 8 equiv of Mn, 0.07 M solutions, THF, rt. c Determined by GC analysis.
d A certain degree of E/Z isomerization is observed. In most cases, the
different isomers obtained in each coupling process could be isolated either
by column chromatography on AgNO3 (20%)-Si gel or by HPLC. For
details, see Experimental Section. e Isolated yield after column chromatog-
raphy. f Performed with 28 equiv of H2O. g Performed with 2.5 equiv of
2,4,6-collidine hydrochloride.
(8) (a) Rasmus, J. E.; Larsen, J.; Skrydstrup, T.; Daasbjerg, K. J. Am.
Chem. Soc. 2004, 126, 7853-7864. (b) Yanlong, Q.; Guisheng, L.; Huang,
Y. J. Organomet. Chem. 1990, 381, 29-34.
(9) (a) Corey, E. J.; Hamanaka, E. J. Am. Chem. Soc. 1964, 86, 1641-
1642. (b) Corey, E. J.; Semmelhack, M. F. Tetrahedron Lett. 1966, 7, 6237-
6240. (c) Corey, E. J.; Semmelhack, M. F. J. Am. Chem. Soc. 1967, 89,
2755-2757. (d) Baker, R. Chem. ReV. 1973, 73, 487-530. (e) Yamamoto,
Y.; Maruyama, K. J. Am. Chem. Soc. 1978, 100, 6282-6284. (f) Clive, D.
L. J.; Anderson, P. C.; Moss, N.; Singh, A. J. Org. Chem. 1982, 47, 1641-
1647. (g) Momose, D.; Iguchi, K.; Sugiyama, T.; Yamada, Y. Tetrahedron
Lett. 1983, 24, 921-924. (h) Calo, V.; Lo´pez, L.; Pesce, G. J. Chem. Soc.,
Perkin Trans. 1 1988, 1301-1304. (i) Rieke, R. D.; Kavaliunas, A. V.;
Rhyne, L. D. J. Am. Chem. Soc. 1979, 101, 246-248. (j) Merijanian, A.;
Mayer, T. J. Org. Chem. 1972, 37, 3945-3947. (k) Benkeser, R. A.
Synthesis 1971, 7, 347-358. (l) Courtois, G.; Miginiac, L. J. Organomet.
Chem. 1974, 69, 1-44. (m) Kitagawa, Y.; Oshima, K.; Yamamoto, H.;
Nozaki, H. Tetrahedron Lett. 1975, 1859-1862. (n) Okude, Y.; Hiyama,
T.; Nozaki, H. Tetrahedron Lett. 1977, 43, 3829-3830. (o) Nakanishi, S.;
Oda, T.; Ueda, T.; Otsuji, Y. Chem. Lett. 1978, 1309-1312. (p) Tokuda,
M.; Satoh, K.; Suginome, H. Chem. Lett. 1984, 6, 1035-1038. (q) Ginah,
F. O.; Donovan, T. A.; Suchan, S. D.; Pfenning, D. R.; Ebert, G. W. J.
Org. Chem. 1990, 55, 584-589. (r) Nishino, T.; Watanabe, T.; Okada, M.;
Nishiyama, Y.; Sonoda, N. J. Org. Chem. 2002, 67, 966-969.
(10) (a) Wu, T.-C.; Hiong, H.; Rieke, R. D. J. Org. Chem. 1990, 55,
5045-5051. (b) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Am. Chem.
Soc. 1991, 113, 5893-5895. (c) Corey, E. J.; Noe, M. C.; Shieh, W.-CH.
Tetrahedron Lett. 1993, 34, 5995-5998.
To account for this result, the following mechanistic
proposals might be postulated: the process would start by a
fast single-electron transfer (SET) from Cp2TiCl (generated
(3) Spencer, R. P.; Schwartz, J. Tetrahedron 2000, 56, 2103-2112.
(4) (a) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988, 110,
8561-8562. (b) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1994,
116, 986-997. (c) Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem.
Soc. 1998, 120, 12849-12859. (d) Gansa¨uer, A.; Pierobon, M.; Bluhm, H.
Synthesis 2001, 16, 2500-2520.
(5) (a) Gansa¨uer, A.; Moschioni, M.; Bauer, D. Eur. J. Org. Chem. 1998,
1923-1927. (b) Gansa¨uer, A.; Bauer, D. Eur. J. Org. Chem. 1998, 2673-
2676.
(6) (a) Cavallaro, C. L.; Schwartz, J. J. Org. Chem. 1995, 60, 7055-
7057. (b) Spencer, R. P.; Schwartz, J. Tetrahedron Lett. 1996, 37, 4357-
4360. (c) Spencer, R. P.; Schwartz, J. J. Org. Chem. 1997, 62, 4204-
4205. (d) Spencer, R. P.; Cavallaro, C. L.; Schwartz, J. J. Org. Chem. 1999,
64, 3987-3995. (e) Hansen, T.; Krintel, S. L.; Daasbjerg, K.; Skrydstrup,
T. Tetrahedron Lett. 1999, 40, 6087-6090. (f) Hansen, T.; Daasbjerg, K.;
Skrydstrup, T. Tetrahedron Lett. 2000, 41, 8645-8649.
(11) This process represented the first direct synthesis of squalene by
the coupling of two (E,E)-farnesyl units.
(12) Procedure used in the opening of oxiranes; see ref 1b.
(13) Existence of η1-allyltitanium species in equilibrium has been
postulated previously: Kasatkin, A.; Nakagawa, T.; Okamoto, S.; Sato, F.
J. Am. Chem. Soc. 1995, 117, 3881-3882.
(7) Davies, S.; Thomas, S. E. Synthesis 1984, 1027-1029.
(14) Zhang, W. Tetrahedron 2001, 57, 7237-7262.
2302
Org. Lett., Vol. 7, No. 12, 2005

Ti(III) (Table 1, entries 5 and 7), the results were no different
from those obtained with 4a and 4b. Thus, the homocoupling
products 5c and 5d were obtained in yields of 84 and 60%,
respectively, and no cyclization products were observed.
One final piece of evidence to denote the presence of the
allyltitanium intermediate (II) was the formation of the
corresponding reduction products15 when 4c and 4d were
made to react with species possessing electrophilic protons
such as H2O and 2,4,6-collidine hydrochloride.
employed might be more easily understood if II is presumed
to associate with a second molecule of the halogenated
derivative 4 via a Lewis acid-base interaction.
To widen the scope of this Ti(III)-catalytic procedure, we
employed the bromo-derivative of geranyl acetate 6. Similar
results were also observed, and a 76% yield of coupling
products was obtained, again as a mixture of R,R′ and R,γ′
isomers (4:1 ratio) (eq 1).
Once we had established the presence of allyltitanium
species as intermediates in this reaction, and bearing in mind
that in these double SET processes Cp2TiClBr is released,
we anticipated that the excess of Mn present in the medium
should permit the regeneration of Ti(III) and thus the process
would be susceptible to catalysis by titanium (Scheme 3).
With these results in mind, we felt that different triterpe-
noids such as squalene, â-onoceradiene (1), and â-onocerin
(2) could be synthesized using this catalytic procedure.16
Thus, squalene was prepared in only one step from farnesyl
bromide with 0.2 equiv of Ti(III) in a yield of 43%. This
process represents a direct and catalytic synthesis of squalene
by the coupling of two (E,E)-farnesyl units.
Scheme 3. Catalytic Cycle
The enantiospecific synthesis of â-onoceradiene (1) was
designed starting from natural (-)-drimenol.17 Following a
protocol reported elsewhere,18 we achieved isomerization of
the double bond to the ∆8 position via the corresponding
formyl derivative. Subsequent reduction and bromination
afforded 8.19 The homocoupling reaction of 8 in the presence
of catalytic quantities of Ti(III) afforded an excellent yield
(87%) of 1 (eq 2).
Thus, we caused 4a-d to react with 0.2 equiv of Cp2TiCl2
and an excess of Mn and found that these reactions took
place rapidly (10-15 min), forming the corresponding
coupling products (5a-d) as expected (Table 1, entries 2,
4, 6, and 8).
These results are in accordance with the proposed absence
of radicals during the coupling process, given that, under
these catalytic conditions, the concentration of radical I
would be much lower and the probability of coupling would
fall significantly versus the much more favorable cyclization
process. It is also worth noting that the yields obtained with
0.2 equiv of Cp2TiCl2 were even higher than those obtained
using the standard protocol (3 equiv of Cp2TiCl2) and that
comparable results were also found when the quantity of
organotitanium was reduced to 0.05 equiv. The fact that
reaction yields did not depend on the quantity of Cp2TiCl2
The optical rotation and spectroscopic data of 1 coincide with
those of the natural product.20 The high regioselectivity
attached to this process, presumably due to the inherent steric
hindrance involved in the formation of the R,γ′ adduct, is
noteworthy.
â-Onocerine (2) was enantioselectively synthesized from
farnesyl acetate according to Scheme 4. Two key steps can
be underlined in this synthesis: the radical cyclization of
(16) Corey and co-workers have recently described a total synthesis of
(+)-R-onocerin, see: Mi, Y.; Schreiber, J. V.; Corey, E. J. J. Am. Chem.
Soc. 2002, 124, 11290-11291. Previous syntheses of onocerane derivatives,
most relying on numerous steps, can be found in references cited in the
above-mentioned paper.
(17) Isolated from the bark of Drimys winteri. Appel, H. H.; Brooks, J.
W.; Overton, K. H. J. Chem. Soc. 1959, 3322-3332.
(18) Ferna´ndez-Mateos, A.; Buro´n, L. M.; Mart´ın de la Nava, E. M.;
Gonza´lez, R. R. J. Org. Chem. 2003, 68, 3585-3592.
(19) Barrero, A. F.; AÄ lvarez-Manzaneda, E. J.; Chahboun, R. Tetrahedron
1998, 54, 5635-5650.
(15) Reaction of 4c with Ti(III) in the presence of water led to the
formation of a 16% yield of methyl (2E,6E)-2,6-dimethyl-2,6-octadienoate.
With 4d, a 12% yield of methyl (2E,6Z)-2,6-dimethyl-2,6-octadienoate was
obtained in the presence of 2,4,6-collidine hydrochloride. In both cases,
the corresponding homocoupling products were also formed (Table 1, entries
9 and 10).
(20) Masuda, K.; Shiojima, K.; Ageta, H. Chem. Pharm. Bull. 1989, 37,
263-265.
Org. Lett., Vol. 7, No. 12, 2005
2303

nation of 11 afforded the corresponding allyl bromide, which
in the presence of catalytic Ti(III) suffered a homocoupling
reaction to give 75% of the corresponding tetracyclic adduct.
Finally, deprotection of the silyl group with TBAF afforded
â-onocerin22 (2) in a yield of 90%.
Scheme 4. Synthesis of â-Onocerin (2)
In conclusion, we present a new catalytic Ti(III)-mediated
method for the homocoupling of allylic halides. It is
noteworthy that the regioselectivity of the process increases
considerably when cyclic allylic halides are used as sub-
strates, as has been demonstrated with the highly efficient
asymmetric synthesis of â-onoceradiene (1) and â-onocerine
(2).
Acknowledgment. This research was supported by the
Spanish Ministry of Science and Technology, Project BQU
2002-03211. Thanks go to our colleague Dr. J. Trout for
revising our English text.
Supporting Information Available: Experimental pro-
1
cedures and spectroscopic data of new compounds and H
and 13C NMR spectra of 1-3, 4c,d, 5a-d, and 6-12. This
material is available free of charge via the Internet at
http://pubs.acs.org.
10S,11-epoxyfarnesyl acetate (9) catalyzed by Ti(III) and the
homocoupling reaction of the corresponding allyl bromide
in the presence of Ti(III) to give product 2. Epoxide 9 was
obtained by the enantioselective cis-dihydroxylation of
farnesyl acetate using AD-mix-â followed by treatment of
the diol with MeSO2Cl-py and base.21 Treatment of epoxide
9 with catalytic Ti(III) afforded the bicyclic alcohol 10 in a
yield of 47%.1a Protection of the secondary hydroxyl group
with TBSCl followed by isomerization of the double bond
via the corresponding aldehyde18 led to alcohol 11. Bromi-
OL050335R
(21) cis-Dihydroxylation of farnesyl acetate using AD-mix-â was previ-
ously reported by Vidari et al. to give the corresponding (10R)-diol in 98%
20
ee; the optical rotation [R]D measured for this compound was +12.3.
See: Vidari, G.; Dapiaggi, A.; Zanoni, G.; Gaslaschelli, L. Tetrahedron
Lett. 1993, 34, 6485-6488. In our hands, this protocol led to similar results;
20
thus, we obtained this diol with an [R]D value of +12.1.
(22) Tanaka, T.; Tanaka, O.; Lin, Z.-W.; Zhou, J.; Ageta, H. Chem.
Pharm. Bull. 1983, 31, 780-783.
2304
Org. Lett., Vol. 7, No. 12, 2005